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1.  Molecular genetics of addiction and related heritable phenotypes: genome wide association approaches identify “connectivity constellation” and drug target genes with pleiotropic effects 
Genome wide association (GWA) can elucidate molecular genetic bases for human individual differences in “complex” phenotypes that include vulnerability to addiction. Here, we review: a) evidence that supports polygenic models with (at least) modest heterogeneity for the genetic architectures of addiction and several related phenotypes; b) technical and ethical aspects of importance for understanding genome wide association data: genotyping in individual samples vs DNA pools, analytic approaches, power estimation and ethical issues in genotyping individuals with illegal behaviors; c) the samples and the data that shape our current understanding of the molecular genetics of individual differences in vulnerability to substance dependence and related phenotypes; d) overlaps between GWA datasets for dependence on different substances; e) overlaps between GWA data for addictions vs other heritable, brain-based phenotypes that include: i) bipolar disorder, ii) cognitive ability, iii) frontal lobe brain volume, iv) ability to successfully quit smoking, v) neuroticism and vi) Alzheimer’s disease. These convergent results identify potential targets for drugs that might modify addictions and play roles in these other phenotypes. They add to evidence that individual differences in the quality and quantity of brain connections make pleiotropic contributions to individual differences in vulnerability to addictions and to related brain disorders and phenotypes. A “connectivity constellation” of brain phenotypes and disorders appears to receive substantial pathogenic contributions from individual differences in a constellation of genes whose variants provide individual differences in the specification of brain connectivities during development and in adulthood. Heritable brain differences that underlie addiction vulnerability thus lie squarely in the midst of the repertoire of heritable brain differences that underlie vulnerability to other common brain disorders and phenotypes.
doi:10.1196/annals.1441.018
PMCID: PMC3922196  PMID: 18991966
pleiotropic; cell adhesion; monte carlo
2.  FUNCTIONAL EXPRESSION OF BRAIN NEURONAL CB2 CANNABINOID RECEPTORS ARE INVOLVED IN THE EFFECTS OF DRUGS OF ABUSE AND IN DEPRESSION 
Major depression and addiction are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of CB2 cannabinoid receptors (CB2-Rs) in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R) but not (H316Y) polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. Using electron microscopy we report the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.
doi:10.1196/annals.1432.036
PMCID: PMC3922202  PMID: 18991891
Neuronal CB2 Cannabinoid Receptors; Brain; electron micrograph; chronic mild stress; anhedonia; depression; drug abuse
3.  Basic and Clinical Immunology of Siglecs 
Siglecs are cell-surface proteins found primarily on hematopoietic cells. By definition, they are members of the immunoglobulin gene super-family and bind sialic acid. Most contain cytoplasmic tyrosine motifs implicated in cell signaling. This review will first summarize characteristics common and unique to Siglecs, followed by a discussion of each human Siglec in numerical order, mentioning in turn its closest murine ortholog or paralog. Each section will describe its pattern of cellular expression, latest known immune functions, ligands, and signaling pathways, with the focus being predominantly on CD33-related Siglecs. Potential clinical and therapeutic implications of each Siglec will also be covered.
doi:10.1196/annals.1443.011
PMCID: PMC3902170  PMID: 19076345
Siglec; human; mouse; leukocyte; ITIM; ITAM; sialic acid; lectin
4.  Retinoic Acid in the Immune System 
Annals of the New York Academy of Sciences  2008;1143:10.1196/annals.1443.017.
On occasion, emerging scientific fields intersect and great discoveries result. In the last decade, the discovery of regulatory T cells (Treg) in immunity has revolutionized our understanding of how the immune system is controlled. Intersecting the rapidly emerging field of Treg function, has been the discovery that retinoic acid (RA) controls both the homing and differentiation of Treg. Instantly, the wealth and breadth of knowledge of the molecular basis for RA action, its receptors, and how it controls cellular differentiation can and will be exploited to understand its profound effects on Treg. Historically, vitamin A deprivation and repletion and RA agonists have been shown to profoundly affect immunity. Now these findings can be interpreted in light of the revelations that RA controls leukocyte homing and Treg function.
doi:10.1196/annals.1443.017
PMCID: PMC3826166  PMID: 19076350
vitamin A; retinoic acid; immune system; tolerance
5.  The Expression of NMDA Receptor Subunit mRNA in Human Chronic Alcoholics 
Annals of the New York Academy of Sciences  2008;1139:10.1196/annals.1432.053.
Ethanol is a modulator at the N-methyl-d-aspartate class of glutamate receptors in the brain. In animal studies the receptor adapts to sustained ethanol exposure through altered expression of the subunits that make up the receptor complex. We used real-time RT-PCR normalized to GAPDH to assay NR1, NR2A, and NR2B subunit mRNA in superior frontal and primary motor cortex tissue obtained at autopsy from chronic alcoholics with and without co-morbid cirrhosis of the liver, and from matched controls. The expression of all three subunits was significantly lower in both areas of cirrhotic alcoholics than in the corresponding areas in both controls and alcoholics without co-morbid disease, who did not differ significantly from each other. The decrease was area-dependent when cases were partitioned by the 5-HTTLPR allele. Thus, polymorphisms in one gene can have a significant effect on the expression of a second, unrelated, gene. The expression of the N-methyl-d-aspartate glutamate receptor complex is under multifactorial control.
doi:10.1196/annals.1432.053
PMCID: PMC3821866  PMID: 18991843
5-HTTLPR; autopsy; glutamate; excitotoxicity; cerebral cortex; genotype–phenotype interactions
6.  Studying the Brain Gut Axis with Pharmacological Imaging 
Annals of the New York Academy of Sciences  2008;1144:10.1196/annals.1418.025.
Pharmacological imaging provides great potential both for evaluating the efficacy of new candidate compounds in the treatment of gastrointestinal symptom-based disorders, and for furthering our understanding of the underlying pathophysiology of such disorders. By combining evaluation of symptoms, behavior, and brain responses to relevant stimuli, use of neuroimaging is able to move the study of brain-gut disorders away from more subjective outcomes and emphasize the underlying neural networks involved in symptom generation and treatment. This chapter reviews the state of the art in pharmacological imaging studies, both in human subjects and in animal models of brain gut interactions.
doi:10.1196/annals.1418.025
PMCID: PMC3817712  PMID: 19076383
Irritable Bowel Syndrome; Brain-Gut axis; neuroimaging; functional gastrointestinal disorder
7.  Role of Increased ROS Dissipation in Prevention of T1D 
Annals of the New York Academy of Sciences  2008;1150:10.1196/annals.1447.045.
Protection of pancreatic β cells is an approach to prevent autoimmune type 1 diabetes (T1D) and to protect transplanted islets. Reactive oxygen species (ROS) are important mediators of β cell death during the development of T1D. We have examined the role of elevated ROS dissipation in the prevention of T1D using the ALR mouse strain. The selection of ALR, for resistance against alloxan-induced free radical–mediated diabetes, led to a strain of mice with an elevated systemic as well as pancreatic ROS dissipation. Independent genetic mapping studies have identified ALR-derived diabetes protective loci. Conplastic and congenic mouse as well as cell line studies have confirmed the genetic mapping and demonstrated that the elevated ROS dissipation protects ALR β cells from autoimmune destruction. Our data support the hypothesis that elevated ROS dissipation protects β cells against autoimmune destruction and prevents T1D development.
doi:10.1196/annals.1447.045
PMCID: PMC3817822  PMID: 19120287
type 1 diabetes; reactive oxygen species; mitochondria; mouse model; genetics
8.  Menstrual Cycle Dysfunction Associated with Neurologic and Psychiatric Disorders 
Epilepsy, bipolar disorder, and migraines are common disorders that are often associated with disturbances in menstrual function in adolescent girls. Women with untreated epilepsy are more likely to have irregular menstrual cycles than are nonepileptic controls, indicating that the disease itself plays a role in the etiology of these reproductive abnormalities. In addition, many girls with these disorders require chronic maintenance treatment with agents that may perturb the hypothalamic-pituitary-ovarian axis. Valproate is a highly effective antiepileptic drug used widely to treat epilepsy, bipolar disorder, and migraines. Valproate induces features of the polycystic ovary syndrome (PCOS) in approximately 7% of women. Girls with epilepsy, and possibly bipolar disorder, appear particularly susceptible to developing PCOS features on valproate, perhaps on account of the relative immaturity of their hypothalamic-pituitary-ovarian axes. Antipsychotics are highly effective drugs used widely to treat adolescents with bipolar disorder, psychotic disorders, and behavioral disturbances. Some, but not all of the antipsychotic, induce hyperprolactinemia, which may result in oligo- or amenorrhea. Prolonged amenorrhea in association with hyperprolactinemia incurs significant risks for bone health in adolescent girls. Because of the potential reproductive health risks associated with use of specific antiepileptic drugs and selective antipsychotics, these agents are vital treatments for adolescents with severe illnesses. Use of these agents should be considered and weighed against the risk of using alternative agents, which have their own side effects, or not treating these serious neurologic and psychiatric disorders.
doi:10.1196/annals.1429.030
PMCID: PMC3773702  PMID: 18574228
bipolar disorder; epilepsy; hypothalamic-pituitary-gonadal (HPG) axis; menstrual cycle dysfunction; migraines; polycystic ovarian syndrome (PCOS); valproate
9.  Cerebral White Matter 
Lesions of the cerebral white matter (WM) result in focal neurobehavioral syndromes, neuropsychiatric phenomena, and dementia. The cerebral WM contains fiber pathways that convey axons linking cerebral cortical areas with each other and with subcortical structures, facilitating the distributed neural circuits that subserve sensorimotor function, intellect, and emotion. Recent neuroanatomical investigations reveal that these neural circuits are topographically linked by five groupings of fiber tracts emanating from every neocortical area: (1) cortico-cortical association fibers; (2) corticostriatal fibers; (3) commissural fibers; and cortico-subcortical pathways to (4) thalamus and (5) pontocerebellar system, brain stem, and/or spinal cord. Lesions of association fibers prevent communication between cortical areas engaged in different domains of behavior. Lesions of subcortical structures or projection/striatal fibers disrupt the contribution of subcortical nodes to behavior. Disconnection syndromes thus result from lesions of the cerebral cortex, subcortical structures, and WM tracts that link the nodes that make up the distributed circuits. The nature and the severity of the clinical manifestations of WM lesions are determined, in large part, by the location of the pathology: discrete neurological and neuropsychiatric symptoms result from focal WM lesions, whereas cognitive impairment across multiple domains—WM dementia—occurs in the setting of diffuse WM disease. We present a detailed review of the conditions affecting WM that produce these neurobehavioral syndromes, and consider the pathophysiology, clinical effects, and broad significance of the effects of aging and vascular compromise on cerebral WM, in an attempt to help further the understanding, diagnosis, and treatment of these disorders.
doi:10.1196/annals.1444.017
PMCID: PMC3753195  PMID: 18990132
fiber tracts; neuropsychiatry; cognition; demyelination; vascular dementia
10.  The Placental Syncytium and the Pathophysiology of Preeclampsia and Intrauterine Growth Restriction 
Preeclampsia is associated with an increased release of factors from the placental syncytium into maternal blood, including the antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluable endoglin, the antifibrinolytic factor plasminogen activator inhibitor-1, prostanoids, lipoperoxides, cytokines, and microparticles. These factors are suggested to promote maternal endothelium dysfunction and are associated with placental damage in pregnancies also complicated with intrauterine growth restriction (IUGR). In this report, we briefly describe the interaction of syncytial factors with hypoxia, reactive oxygen species, and apoptosis in the pathophysiology of preeclampsia and IUGR. Given the critical role of the syncytium in these complications of pregnancy, we also present a novel methodology in which laser capture microdissection followed by Western blotting is used to assess levels of syncytial Fas ligand, a key protein in the apoptotic cascade.
doi:10.1196/annals.1434.015
PMCID: PMC3671376  PMID: 18443340
Placenta; syncytiotrophoblast; reactive oxygen species; apoptosis; Fas ligand; pathophysiology of preeclampsia; IUGR; laser capture microdissection
11.  Corticosterone Regulates pERK1/2 Map Kinase in a Chronic Depression Model 
Neurotransmitter- or neurotrophin-regulated intracellular signaling in the hippocampus is hypothesized to contribute to depression and antidepressant (ADT) efficacy. Extracellular signal-regulated kinase 1/2 (ERK1/2) is downstream of several receptor types and regulates transcriptional activity of many targets; ERK1/2 may thereby influence mood and affect. Using a novel, ADT-sensitive depression model in mice, we show that prior corticosterone exposure decreases motivated behavior, sucrose consumption, and pERK1/2 in the dentate gyrus, but not in CA1/CA3. Notably, prefrontal cortical targets were also regulated. Our data suggest ADTs restore hippocampal pERK1/2 after stress-related insult, and potentially reveal a novel role for prefrontal neurotrophins in depressive-like symptomology.
doi:10.1196/annals.1410.076
PMCID: PMC3657205  PMID: 19120149
stress; antidepressant; anhedonia; prefrontal cortex; BDNF; dentate gyrus; amitriptyline; fluoxetine
12.  Monitoring the State of Cholecystokinin Receptor Oligomerization after Ligand Binding Using Decay of Time-Resolved Fluorescence Anisotropy 
Oligomeric complexes of G protein–coupled receptors (GPCRs) are now commonly recognized and can provide a mechanism for regulation of signaling systems. Receptor oligomerization has been most extensively studied using coimmunoprecipitation and bioluminescence or fluorescence resonance energy-transfer techniques. Here, we have utilized decay of time-resolved fluorescence anisotropy of yellow fluorescent protein-labeled cholecystokinin receptor constructs to examine the state of oligomerization of this receptor in living cells. The rotational correlation times established that the cholecystokinin receptor is constitutively present in an oligomeric state that is dissociated in response to agonist occupation. In contrast, antagonist occupation failed to modify this signal, leaving the oligomeric structure intact. This dynamic technique complements the other biochemical and steady-state fluorescence techniques to establish the presence of oligomeric receptor complexes in living cells.
doi:10.1196/annals.1418.004
PMCID: PMC3580951  PMID: 19076359
G protein–coupled receptors; cholecystokinin receptor; receptor oligomerization; time-resolved anisotropy; rotational dynamics
13.  Vitamin C–mediated Maillard Reaction in the Lens Probed in a Transgenic-mouse Model 
Aging human lens crystallins are progressively modified by yellow glycation, oxidation, and cross-linked carbonyl compounds that have deleterious properties on protein structure and stability. In order to test the hypothesis that some of these compounds originate from oxidized vitamin C, we have overexpressed the human vitamin C transporter 2 (hSCVT2) in the mouse lens. We find that levels of ascorbic and dehydroascorbic acid are highly elevated compared to the wild type and that the lenses have accumulated yellow color and advanced Maillard reaction products identical with those of the human lens. Treatment of the mice with nucleophilic inhibitors can slow down the process, opening new avenues for the pharmacological prevention of senile cataractogenesis.
doi:10.1196/annals.1433.064
PMCID: PMC3485640  PMID: 18448816
glycation; ascorbic acid; crystallin; cross-linking; aging
14.  Recent Structural and Mechanistic Insights into Endplate Acetylcholine Receptors 
Voluntary movement mediated by skeletal muscle relies on endplate acetylcholine receptors (AChR) to detect nerve-released ACh and depolarize themuscle fiber. Recent structural and mechanistic studies of the endplate AChR have catalyzed a leap in our understanding of the molecular steps in this chemical-to-electrical transduction process. Studies of acetylcholine binding protein (AChBP) give insight into ACh recognition, the first step in activation of the AChR. An atomic structural model of the Torpedo AChR at a resolution of 0.4 nm, together with single-ion channel recording methods, allow tracing of the link between the agonist binding event and gating of the ion channel, as well as determination of how the channel moves when it opens to allow flow of cations. Structural models of the human AChR enable precise mapping of disease-causing mutations, while studies of the speed with which single AChR channels open and close cast light on pathogenic mechanisms.
doi:10.1196/annals.1405.041
PMCID: PMC3478106  PMID: 18567853
acetylcholine receptor; acetylcholine binding protein; agonist recognition; binding-gating coupling mechanism; congenital myasthenic syndrome
15.  Further Observations in Congenital Myasthenic Syndromes 
During the past five years many patients suffering from congenital myasthenic syndromes (CMS) have been identified worldwide and novel causative genes and mutations have been discovered. The disease genes now include those encoding each subunit of the acetylcholine receptor (AChR), the ColQ part of acetylcholinesterase (AChE), choline acetyltransferase, Nav 1.4, MuSK, and Dok-7. Moreover, emerging genotype-phenotype correlations are providing clues for targeted mutation analysis. This review focuses on the recent observations in selected CMS.
doi:10.1196/annals.1405.039
PMCID: PMC3478107  PMID: 18567859
congenital myasthenic syndromes; acetylcholinesterase; choline acetyltransferase; acetylcholine receptor; Dok-7
16.  Lymphatic Involvement in Lymphangioleiomyomatosis 
Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease affecting primarily premenopausal women. The disease is characterized by cystic lung disease, at times leading to respiratory compromise, abdominal tumors (in particular, renal angiomyolipomas), and involvement of the axial lymphatics (e.g., adenopathy, lymphangioleiomyomas). Disease results from the proliferation of neoplastic cells (LAM cells), which, in many cases, have a smooth muscle cell phenotype, express melanoma antigens, and have mutations in one of the tuberous sclerosis complex genes (TSC1 or TSC2). In the lung, LAM cells found in the vicinity of cysts are, at times, localized in nodules and may be responsible for cyst formation through the production of proteases. Lymphatic channels, expressing characteristic lymphatic endothelial cell markers, are found within the LAM lung nodules. LAM cells may also be localized within the walls of the axial lymphatics, and, in some cases, penetrate the wall and proliferate in the surrounding adipose tissue. Consistent with extensive lymphatic involvement in LAM, the serum concentration of VEGF-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers.
doi:10.1196/annals.1413.018
PMCID: PMC3392168  PMID: 18519973
lymphangiogenesis; metastasis; lymphangioleiomyomatosis; VEGF-D; VEGF-C
17.  Rebooting the Immune System with High-Dose Cyclophosphamide for Treatment of Refractory Myasthenia Gravis 
A small but important proportion of patients with myasthenia gravis (MG) are refractory to conventional immunotherapy. We have treated 12 such patients by “rebooting” the immune system with high-dose cyclophosphamide (Hi Cy, 200 mg/kg), which largely eliminates the mature immune system, while leaving hematopoietic precursors intact. The objective of this report is to describe the clinical and immunologic results of Hi Cy treatment of refractory MG. We have followed 12 patients clinically for 1–9 years, and have analyzed their humoral and cellular immunologic parameters. Hi Cy is safe and effective. All but one of the patients experienced dramatic clinical improvement for variable periods from 5 months to 7.5 years, lasting for more than 1 year in seven of the patients. Two patients are still in treatment-free remission at 5.5 and 7.5 years, and five have achieved responsiveness to immunosuppressive agents that were previously ineffective. Hi Cy typically reduced, but did not completely eliminate, antibodies to the autoantigen AChR or to tetanus or diphtheria toxin; re-immunization with tetanus or diphtheria toxoid increased the antibody levels. Despite prior thymectomy, T cell receptor excision circles, generally considered to reflect thymic emigrant T cells, were produced by all patients. Hi Cy treatment results in effective, but often not permanent, remission in most refractory myasthenic patients, suggesting that the immune system is in fact “rebooted,” but not “reformatted.” We therefore recommend that treatment of refractory MG with Hi Cy be followed with maintenance immunotherapy.
doi:10.1196/annals.1405.033
PMCID: PMC3390145  PMID: 18567882
myasthenia gravis; refractory MG; high-dose cyclophosphamide; Hi Cy; rebooting the immune system; TRECs; autoimmunity; immunotherapy
18.  Endometriosis and Tissue Factor 
Tissue factor (TF), is a cellular receptor that binds the ligand factor VII/VIIa to initiate the blood coagulation cascade. In addition to its role as the initiator of the hemostatic cascade, TF is known to be involved in angiogenesis via an interaction with factor VIIa and protease-activated receptor-2 (PAR-2). In this article we review previous studies from our laboratory demonstrating that the pattern and level of TF expression is altered in multiple cell types derived from eutopic and ectopic endometrium from women with endometriosis compared with normal endometrium. We posit that the inflammatory environment that occurs in ectopic and eutopic endometrium from patients with disease results in high TF expression that in turn, signals via PAR-2 to further produce inflammatory cytokine or chemokine production and macrophage recruitment. Thus, our studies suggest that TF might be an ideal target for therapeutic intervention in endometriosis.
doi:10.1196/annals.1434.008
PMCID: PMC3129033  PMID: 18443336
endometriosis; endometrium; tissue factor
19.  Stem Cells and the Pathogenesis of Endometriosis 
Endometriosis is a common gynecological disorder that is defined by the presence of endometrial tissue outside the uterine cavity. This disease often results in extensive morbidity, including chronic pelvic pain and infertility. The pathogenesis of endometriosis is likely multifactorial, and extensive investigation has explored the role of genetics, environmental factors, and the immune system in predisposing patients to developing endometriosis. A series of recent publications have described the identification of endometrial stem/progenitor cells. Such cells have long been speculated to function in the cyclic regeneration of the endometrium during the menstrual cycle and in the pathogenesis of several gynecological disorders. This narrative review will (i) examine the evidence for endometrial stem cells, (ii) examine their potential role in the pathogenesis of endometriosis, and (iii) identify important unanswered questions with suggestions for future investigation.
doi:10.1196/annals.1434.014
PMCID: PMC3107843  PMID: 18443337
Endometrium; endometriosis; stem cells; bone marrow; uterus
20.  New Horizons for Imaging Lymphatic Function 
In this review, we provide a comprehensive summary of noninvasive imaging modalities used clinically for the diagnosis of lymphatic diseases, new imaging agents for assessing lymphatic architecture and cancer status of lymph nodes, and emerging near-infrared (NIR) fluorescent optical imaging technologies and agents for functional lymphatic imaging. Given the promise of NIR optical imaging, we provide example results of functional lymphatic imaging in mice, swine, and humans, showing the ability of this technology to quantify lymph velocity and frequencies of propulsion resulting from the contractility of lymphatic structures.
doi:10.1196/annals.1413.002
PMCID: PMC3094766  PMID: 18519956
lymph flow; NIR optical imaging; fluorescence; indocyanine green
21.  Immunoregulatory Pathways Controlling Progression of Autoimmunity in NOD Mice 
The activation, expansion, and survival of regulatory T cells (Tregs) as well as the expression of their suppressive capacities result from distinct signaling pathways involving various membrane receptors and cytokines. Multiple studies have shown that thymus-derived naturally occurring Tregs constitutively express the forkhead/winged helix transcription factor FoxP3 in addition to high levels of CD25, the negative co-stimulatory molecule CTLA-4, and the glucocorticoid-induced TNF receptor-related protein GITR. At variance, adaptive or induced Tregs acquire these phenotypic markers as they differentiate in the periphery, following adequate stimulation in the appropriate environment, together with their capacity to produce immunomodulatory cytokines (mainly, IL-4, IL-10 and TGF-β) and to display regulatory capacities. However, none of these molecules but FoxP3 are restricted to Tregs since they may also be expressed and upregulated on activated effector T cells. This explains why different hypotheses were proposed to interpret interesting reports showing that in vivo abrogation of CTLA-4 signaling using neutralizing CTLA-4 antibodies triggers different autoimmune or immune-mediated manifestations. Thus, an effect on pathogenic T cell effectors and/or Tregs has been proposed. Here we present and discuss recent results we obtained in the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes, arguing for a key role of CTLA-4 in the functional activity of Tregs. Moreover, data are presented that simultaneous blockade of CTLA4 and TGF-β further impairs immunoregulatory circuits that control disease progression.
doi:10.1196/annals.1447.046
PMCID: PMC3087168  PMID: 19120317
CTLA-4; TGF-β; NOD; autoimmune diabetes; regulatory T cells
22.  Antibiotic clearance of Ehrlichia canis from dogs infected by intravenous inoculation of carrier blood 
Ehrlichia canis is the etiologic agent of canine monocytic ehrlichiosis (CME) and is a useful model for tick-borne zoonotic pathogens, many of which infect dogs. The purpose of this study was to evaluate rifampin and doxycycline regimens for clearance of E. canis infections in addition to alleviation of CME. Beagles were infected with E. canis by intravenous inoculation with carrier blood and treated with either rifampin or doxycycline after the acute phase of CME. Improved hematological values demonstrated that both treatments effectively relieved signs of the disease. Peripheral blood from all dogs became PCR-negative after antibiotic treatment, suggesting that these infections were eliminated and that rifampin is an effective alternative chemotherapeutic agent for treatment of CME.
doi:10.1196/annals.1428.087
PMCID: PMC3052985  PMID: 19120226
Ehrlichia canis; Rhipicephalus sanguineus; ehrlichiosis; doxycycline; rifampin
23.  Pathological evidence of ehrlichiosis among calves inoculated with Ehrlichia chaffeensis 
An immunocompetent animal disease model based on infection with Ehrlichia chaffeensis would facilitate research toward understanding mechanisms responsible for the broad range of clinical signs associated with human monocytic ehrlichiosis (HME). Adaptability to experimental feeding of various tick species and stages and to testing therapies comparable to those for human diseases are additional advantages of large animal models. Herein we summarize pathology reports for calves that developed fatal disease after experimental inoculation with E. chaffeensis. Elevated liver enzyme levels and lung pathology among these deceased calves corroborated earlier reports of severe HME. Thus, an experimental disease model based on infection of outbred immunocompetent hosts with E. chaffeensis could be within our grasp for the first time.
doi:10.1196/annals.1428.068
PMCID: PMC3053141  PMID: 19120184
Ehrlichia chaffeensis; human monocytic ehrlichiosis; large animal disease model
24.  Protein Kinases and Addiction 
Although drugs of abuse have different chemical structures and interact with different protein targets, all appear to usurp common neuronal systems that regulate reward and motivation. Addiction is a complex disease that is thought to involve drug-induced changes in synaptic plasticity due to alterations in cell signaling, gene transcription, and protein synthesis. Recent evidence suggests that drugs of abuse interact with and change a common network of signaling pathways that include a subset of specific protein kinases. The best studied of these kinases are reviewed here and include extracellular signal-regulated kinase, cAMP-dependent protein kinase, cyclin-dependent protein kinase 5, protein kinase C, calcium/calmodulin-dependent protein kinase II, and Fyn tyrosine kinase. These kinases have been implicated in various aspects of drug addiction including acute drug effects, drug self-administration, withdrawal, reinforcement, sensitization, and tolerance. Identifying protein kinase substrates and signaling pathways that contribute to the addicted state may provide novel approaches for new pharma-cotherapies to treat drug addiction.
doi:10.1196/annals.1441.022
PMCID: PMC3050040  PMID: 18991950
protein kinase; addiction; extracellular signal-regulated kinase; cAMP-dependent protein kinase; cyclin-dependent protein kinase 5; protein kinase C; calcium/calmodulin-dependent protein kinase II; Fyn tyrosine kinase
25.  Receptor for Advanced Glycation End Products 
The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed onmultiple cell types implicated in the immune–inflammatory response and in atherosclerosis. Multiple studies have elucidated that ligand–RAGE interaction on cells, such as monocytes, macrophages, and endothelial cells, mediates cellular migration and upregulation of proinflammatory and prothrombotic molecules. In addition, recent studies reveal definitive rules for RAGE in effective T lymphocyte priming in vivo. RAGE ligand AGEs may be formed in diverse settings; although AGEs are especially generated in hyperglycemia, their production in settings characterized by oxidative stress and inflammation suggests that these species, in part via RAGE, may contribute to the pathogenesis of atherosclerosis. In murine models of atherosclerosis, vascular inflammation is a key factor and one which is augmented, in parallel with even further increases in RAGE ligands, in diabetic macrovessels. The findings that antagonism and genetic disruption of RAGE in atherosclerosis-susceptible mice strikingly reduces vascular inflammation and atherosclerotic lesion area and complexity link RAGE intimately to these processes and suggest that RAGE is a logical target for therapeutic intervention in aberrant inflammatory mechanisms and in atherosclerosis.
doi:10.1196/annals.1433.056
PMCID: PMC3049155  PMID: 18448789
receptor for advanced glycation end products; inflammation; atherosclerosis; adaptive immunity; T cell priming

Results 1-25 (114)